Vantage Snippets are short summaries of breaking news stories.
The determination of UK-based liquid biopsy developer Oncimmune to boost its top line by signing up partners is a matter of record, and its latest deal is a significant one. The company has formed a US distribution deal for its EarlyCDT-Lung assay with the blood testing group Biodesix, worth $28m over five years. Biodesix will also buy Oncimmune’s US operations, including its Clia lab, chiming with Biodesix’s own ambitions of becoming a serious lung cancer diagnostics player. EarlyCDT-Lung has been sold in the US since 2012 to help pulmonologists rule out treatment for patients with benign lung masses. But Oncimmune is pushing for the test to be used as a screening tool, and top-line data from the 12,210-patient ECLS study, released last month, point in the right direction, though details are scant. The trial met its primary endpoint, Oncimmune said, showing that use of EarlyCDT-Lung with subsequent X-ray and CT imaging reduced the incidence of patients with late-stage lung cancer or unclassified presentation at diagnosis, compared with standard practice. Further data ought to come in autumn, but Oncimmune will need to definitively show the test’s cost-effectiveness to build meaningful sales on either side of the Atlantic.
From ship-building to solar energy, the South Korean concern HLB Company Ltd has its fingers in numerous pies. Today its investors got confirmation that much of its value actually derives from a 65% stake in the private US/Korean company LSK Biopharma. This is because LSK’s lead asset, rivoceranib, failed to improve overall survival in Angel, its international phase III trial in gastric cancer, and the setback caused HLB’s stock to lose 30%, or about $730m in market cap terms. HLB had built a stake in LSK over a few years, and is understood to have recently topped up its holding with the purchase of a 7% interest at a valuation of $300m. Rivoceranib, meanwhile, has a curious history: it is a somewhat obscure VEGFr2 kinase inhibitor originated by another private US group, Advenchen Laboratories, and previously known under the generic name apatinib. In 2014 it was launched as Aitan in China for gastric cancer by Jiangsu Hengrui Medicine, with whose anti-PD-1 MAb camrelizumab it is separately being combined in a front-line gastric cancer trial. LSK says it is continuing rivoceranib studies in this and other settings.
|Studies of rivoceranib/apatinib involving US clinics|
|Phase III (Angel)||Monotherapy vs placebo, ≥2nd-line gastric cancer||Failed to improve OS||NCT03042611|
|Phase I/II (Appease)||Keytruda combo, previously treated urothelial, MSI-H/dMMR & gastric cancers||Data 2023||NCT03407976|
|Phase I||Opdivo combo, various cancers||Data Sep 2019||NCT03396211|
|Unclear||Camrelizumab combo, first-line gastric cancer||Study cleared to begin Apr 2019||None|
|Source: company announcements & clinicaltrials.gov.|
An apparent success in the first-line SCLC Caspian trial could give Imfinzi a new use and allow it to challenge Roche in a setting where Tecentriq secured a US label in March. How well Astra’s drug might compete will not become apparent until the full data are revealed at an upcoming conference, and until a rival first-line study of Merck & Co’s Keytruda, Keynote-604, reads out in December. Keytruda recently scored a third-line US approval, joining Bristol-Myers Squibb’s Opdivo in a setting that could soon be rendered obsolete. Though nothing about the magnitude of Caspian’s overall survival benefit has been revealed, one aspect of the interim result is especially intriguing: Astra says the Imfinzi plus chemo cohort yielded statistical significance versus chemo alone, but does not mention how subjects fared on Imfinzi plus tremelimumab and chemo. This omission suggests that the tremelimumab combo arm might have failed, and if tremelimumab toxicity is accelerating patient deaths this should raise fresh doubts about the relevance of adding CTLA4 inhibition into the mix. Performance of this cohort, and the extent to which survival was driven by PD-L1-positive subjects, should be scrutinised closely.
|Selected first-line SCLC trials|
|Drug||Company||Study||Setting||mOS result||Trial ID|
|Opdivo||Bristol-Myers Squibb||Checkmate-451||+ Yervoy + chemo vs chemo||Failed (HR=0.92, p=0.3693)||NCT02538666|
|On top of chemo||Failed (HR=0.84)|
|Tecentriq||Roche||Impower-133||On top of chemo||12.3mth vs 10.3mth (HR=0.70, p=0.007)||NCT02763579|
|Imfinzi||Astrazeneca||Caspian||+ tremelimumab + chemo vs chemo||Not commented on||NCT03043872|
|On top of chemo||Statistically & clinically significant|
|Keytruda||Merck & Co||Keynote-604||On top of chemo||Due Dec 2019||NCT03066778|
Credit to Aldeyra Therapeutics for discontinuing development of its lead project, reproxalap, in noninfectious anterior uveitis after yesterday’s phase III flop. But the company has more lucrative uses in mind for the asset, and it will hope that the latest data do not bode ill in dry eye disease and allergic conjunctivitis. Aldeyra highlighted the differences between the disorders during yesterday’s conference call, but the gains the group’s stock made in March when it reported positive data in allergic conjunctivitis have now been erased. The next readout will involve a topical dermal formulation of reproxalap in Sjögren-Larsson syndrome, but the big one is the Renew trial in dry eye disease; a potentially longer-lasting formulation of the eyedrop is also in phase II in dry eye. Aldeyra has not nailed down details of its second phase III study in allergic conjunctivitis, but seems convinced that the FDA will agree to an allergen chamber trial, which would be less risky than a study involving natural exposure to pollen during the allergy season. Aldeyra will meet the agency in the second half and report back; any change in its plans could see it punished again.
|Eyeing new markets: reproxalap's key trials|
|Trial name||Setting||Trial ID||Data due||2024e indication sales ($m)|
|Solace||Noninfectious anterior uveitis||NCT03131154||Failed||1|
|Reset||Sjögren-Larsson Syndrome||NCT03445650||Part 1 data H2 2019||-|
|Phase II study (new formulation)||Dry eye disease||NCT03916042||H2 2019/early 2020||182|
|Renew||Dry eye disease||NCT03879863||Part 1 data late 2019/early 2020|
|Source: EvaluatePharma, clinicaltrials.gov.|
Seltorexant seems to be the asset that just keeps giving, as seen by the 40% lift in Minerva Neurosciences' shares yesterday. The project not only proved itself to be effective at sleep initiation and maintenance, but also beat the leading sleep brand, Ambien, in a 365-patient phase IIb trial. Seltorexant, an orexin 2 receptor agonist, is designed to mimic natural sleep by damping down mechanisms that promote excessive wakefulness. The results of the sleep trial come before phase IIb data for seltorexant as an add-on for patients with major depressive disorder, due in the third quarter. The question for Minerva, which is co-developing the project with J&J, is which of the 5mg, 10mg and 20mg doses to move into pivotal trials. While all three showed efficacy in the insomnia study, 20mg performed best on all sleep measures. However, Minerva is expected to take the low doses forward too, as one of the biggest and growing markets for sleep products are the elderly, a population where regulators are keen to find the lowest effective doses. Sellside forecasts from Evaluate see seltorexant achieving sales of $65m in 2024, but given the latest data upgrades to commercial and regulatory chances could follow.
Undeterred by the cautious tone of last week’s NEJM paper on evobrutinib’s phase II data in multiple sclerosis Merck KGaA is to press ahead with a pivotal trial of this BTK inhibitor. Luciano Rossetti, Merck’s head of R&D, told Vantage that the group had agreed with regulators on a single dose to take forward; presumably this is 75mg once daily, though he would not confirm this. The paper had raised questions about statistical significance, but Mr Rossetti insisted that this was down to the NEJM applying to phase II “the same statistical criteria that you would use in a larger phase III” study. In fact, he argued, using rigorous p values in initial trials like evobrutinib’s was “extremely faulty”. One consideration in picking a phase III dose is liver enzyme elevations seen in phase II, which Mr Rossetti accepted were important and needed to be monitored. It is still not clear why so few other BTK players are looking at multiple sclerosis; Mr Rossetti noted that the shift to highly selective inhibitors like evobrutinib was recent, adding: “I would not be surprised if after our success ... there was a lot more interest.”
Amag got an unexpected US thumbs up for its female hypoactive sexual desire disorder (HSDD) project Vyleesi on Friday. But the bigger question is whether there will be a market for the drug, or if it will go the same way as Sprout Pharmaceuticals’ Addyi, which reportedly sold just $13m at its 2016 peak. Apart from the questionable efficacy of Vyleesi – the FDA noted no difference between the drug and placebo in the number of satisfying sexual events in phase III – side effects might hold back sales. Patients are meant to inject Vyleesi at least 45 minutes before having sex, but their plans could be scuppered by nausea, which was reported in 40% of subjects, often within an hour of dosing. At least Vyleesi can be taken alongside alcohol, unlike Addyi. Still, the main question is whether female HSDD is even a disease. Leerink analysts estimated that around six million premenopausal women are affected, but admitted that 95% do not know that they have a medical condition. This did not stop them saying Vyleesi could make $90m by 2025. Amag’s stock climbed 18% in premarket trading this morning while Vyleesi's originator, Palatin, was up 50%; however both stocks were in the red later today.
|Vyleesi vs Addyi|
|Product||Company||Mechanism||Delivery||Warnings||2024e sales ($m)|
|Addyi||Sprout Pharmaceuticals||5-HT1A agonist & 5-HT2A antagonist||Oral, once daily||Severe hypotension and syncope risk with alcohol & CYP3A4 inhibitors (black box warning); only available through REMS programme||-|
|Vyleesi||Amag/Palatin||Melanocortin 4 agonist||Subcutaneous injection, as needed||Transient hypertension, focal hyperpigmentation, nausea||151|
|Source: EvaluatePharma, product labels.|
If Bristol-Myers Squibb was not facing enough investor disquiet over its $74bn takeout of Celgene, the FTC piled on even more misery today by ordering Bristol to ditch the psoriasis drug Otezla as a condition of getting the deal across the finish line. This is undoubtedly a blow, as seen by the 7% fall in Bristol shares in early trading. Otezla, Celgene's third-biggest drug, was one of the things that had made the pricey looking deal vaguely palatable. This leaves Bristol with BMS-986165 as its brightest hope in psoriasis and other inflammatory disorders. BMS-986165 is one of the most advanced Tyk2 projects in development today and, while phase II trials have suggested that it could even be better than Otezla, having the approved blockbuster on the books as well would have been preferable to investors. Bristol tried to put positive spin on the news today, reconfirming that the merger was still on, but with a delay. The transaction is now expected to close either at the end of 2019 or the beginning of 2020, but those already questioning the move between the two groups will have even more ammunition.
|Otezla versus BMS-986165|
|Product||Company||Mechanism of action||2018||2024e||Phase||First launch|
|Otezla||Celgene||PDE4 inhibitor||1,608||2,402||Marketed||April 2014|
|BMS-986165||Bristol-Myers Squibb||Tyrosine kinase 2 inhibitor||-||882||Phase III||Dec 2021|
Regeneron and Sanofi have claimed a win in the first proof-of-concept trial with their anti-IL-33 MAb REGN3500 (SAR440340), a potential successor to Dupixent. However, REGN3500 merely beat placebo in the phase II asthma trial. The study also included the anti-IL-4/IL-13 MAb Dupixent, which numerically beat the newcomer, while a combination of the two agents did not outperform Dupixent alone. The data raise questions about whether further development of REGN3500 is worthwhile but, perhaps more importantly, look like bad news for Anaptysbio, whose lead project, etokimab, also hits IL-33. Anaptysbio, which is awaiting readout of the Atlas trial in atopic dermatitis, saw its stock open down 15% today. The latest data suggest that IL-33-targeting drugs could at best be similar to Dupixent. If this is borne out in Atlas etokimab would find it difficult to compete in what are crowded sectors. As well as atopic dermatitis the company is taking aim at asthma, where Dupixent is already approved, and nasal polyps, where it soon could be. Glaxosmithkline might also want to re-evaluate its anti-IL-33 contender, GSK3772847, which it previously highlighted as its most promising respiratory project.
|As good, but not better? The IL-33 pipeline|
|Atopic dermatitis||NCT03736967, NCT03738423||Both Mar 2020|
|Etokimab||Anaptysbio||Atopic dermatitis||Atlas, NCT03533751||Jun 2019|
|Nasal polyps||NCT03614923||Dec 2019|
|Asthma||PhIIb planned this year||-|
|GSK3772847||Glaxosmithkline/J&J||Asthma||NCT03207243, NCT03393806||Feb 2019, Oct 2019|
|Source: EvaluatePharma, clinicaltrials.gov.|
Welcome to the newest cult biotech stock: Bellus Health, a Canadian group with a long history of reinvention, closed up 45% yesterday after Merck & Co highlighted the phase III chronic cough project gefapixant at its R&D day. The connection is that gefapixant shares its mechanism of action, purinergic receptor P2X3 antagonism, with Bellus’s BLU-5937. That asset became Bellus’s lead after the pivotal failure in 2016 of eprodisate in AA amyloidosis, an event that came some years after a US complete response letter and the earlier phase III blow-up of the Alzheimer’s disease project tramiprosate. Back then the group was known as Neurochem, and the tramiprosate prodrug BLU8499/ALZ-801 is now in development by Alzheon. Meanwhile, the rationale behind BLU-5937 and gefapixant is that P2X3 receptors might be implicated in respiratory disorders; but chronic cough could have a variety of underlying causes, including asthma, infection, gastrointestinal conditions and drug side effects, so designing a robust trial with a relevant endpoint will be problematic. Still, even after yesterday’s surge Bellus’s valuation only just breached $300m, which in the current climate might make it worth a punt.
|Industry P2X3 antagonist pipeline|
|Gefapixant||Merck & Co (ex Afferent/Roche)||Phase III (NCT03696108)|
|S-600918||Shionogi||Phase II (Japan)|
|BLU-5937||Bellus Health (ex Astrazeneca)||Phase II (NCT03979638)|
|BAY1902607||Bayer||Phase I/II (NCT03535168)|
|BAY1817080||Bayer/Evotec||Phase I/II (NCT03310645)|
|ASN009||Asana BioSciences||Likely discontinued|
|Source: EvaluatePharma & clinicaltrials.gov.|